The preferential replication of HIV in Th2 and Th0 cells over Th1 cells has been recently proposed to occur during the development of AIDS. To address this question, we have infected human T helper (Th) clones, developed from different normal donors, with different HIV isolates and examined all differences in HIV fusion, entry, and infectivity. Our studies has demonstrated that human T cells and antigen-specific T cell clones express significant levels of several chemokine receptors on their surface which mediate T-cell trafficking, degranulation, and intracellular calcium mobilization as well as serving as co-receptors mediating HIV-1 entry into these cell populations. However, despite these differences in chemokine receptor expression, our studies have demonstrated that human Th0, Th1, and Th2 clones are all capable of being infected with the various T-, M-, and dual-tropic HIV-1 strains. HIV-1-infected Th1 clones exhibit a rapid (1-5 day) Fas-mediated apoptosis in vitro compared to infected Th2 clones (4-21 days). The increased expression of Fas ligand on the surface of Th1 but not Th2 clones post HIV-1 infection may possibly explain the more rapid turnover of this CD4+ T cell subset. Further examination of the various apoptotic-signaling differences between human Th1 and Th2 clones revealed that the majority of human Th1 but not Th2 cells are susceptible to activation-induced cell death (AICD). In addition, the majority of human Th1 clones expressed little to no bcl-2 and bcl-xl (anti-apoptotic proteins) making them more susceptible to various apoptotic stimuli as well as HIV-1-mediated cell death. In contrast, human Th2 clones express higher levels of bcl-2 and bcl-xl and were found to be less susceptible to apoptosis and HIV-1-mediated cytopathic effects. Thus, the protection of bcl-expressing T cells from HIV- induced cell death suggests that apoptosis not only contributes to cell killing by HIV infection but may also permit the selective destruction of Th1 cells in the periphery leading to an increase in circulating Th2-like lymphocytes. This increased susceptibility of Th1 clones to HIV-mediated cell death suggests a major mechanism for HIV-induced immunosuppression in AIDS. Our findings that Th1 and Th2 clones also differ in the expression of certain cell surface chemokine receptor may account for the increased susceptibility of Th subsets. We believe that a Th0-Th1 to Th2 switch occurs during many chronic inflammatory disease as well as aging. We propose that CD4+ T helper cells and clones, without any exogenous influence from cytokines, derived from the peripheral blood of older individuals may be more permissive to T cell tropic HIV-1 infections compared to lymphocytes derived from younger donors. The Clinical Immunology Section will attempt to directly examine this question. The objective of the proposed project is to further define the differences in T cell-, monocyte-, and dual-tropic HIV-1 replication in T cells derived from young and old donors as well as in human Th1 and Th2 clones. The relationship between T cell susceptibility to HIV-1 infectivity and apoptosis will be further examined using various cytokines (i.e. IgF1, IL-4) and signaling inhibitor agents (ie caspase and kinase inhibitors) to hinder HIV-1 infectivity. Finally, we will examine the signaling and gene expression requirements of HIV-1 and its glycoproteins for virus interactions and infectivity of T lymphocytes. - HIV, Chemokines, Elderly, T cells, Th1, Th2, Co-Receptors